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Open Access 01-12-2018 | Research article

Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis

Authors: Emese Balogh, Douglas J. Veale, Trudy McGarry, Carl Orr, Zoltan Szekanecz, Chin-Teck Ng, Ursula Fearon, Monika Biniecka

Published in: Arthritis Research & Therapy | Issue 1/2018

Abstract

Background

In this study, we examined the effect of oxidative stress on cellular energy metabolism and pro-angiogenic/pro-inflammatory mechanisms of primary rheumatoid arthritis synovial fibroblast cells (RASFC) and human umbilical vein endothelial cells (HUVEC).

Methods

Primary RASFC and HUVEC were cultured with the oxidative stress inducer 4-hydroxy-2-nonenal (4-HNE), and extracellular acidification rate, oxygen consumption rate, mitochondrial function and pro-angiogenic/pro-inflammatory mechanisms were assessed using the Seahorse analyser, complex I–V activity assays, random mutation mitochondrial capture assays, enzyme-linked immunosorbent assays and functional assays, including angiogenic tube formation, migration and invasion. Expression of angiogenic growth factors in synovial tissue (ST) was assessed by IHC in patients with rheumatoid arthritis (RA) undergoing arthroscopy before and after administration of tumour necrosis factor inhibitors (TNFi).

Results

In RASFC and HUVEC, 4-HNE-induced oxidative stress reprogrammed energy metabolism by inhibiting mitochondrial basal, maximal and adenosine triphosphate-linked respiration and reserve capacity, coupled with the reduced enzymatic activity of oxidative phosphorylation complexes III and IV. In contrast, 4-HNE elevated basal glycolysis, glycolytic capacity and glycolytic reserve, paralleled by an increase in mitochondrial DNA mutations and reactive oxygen species. 4-HNE activated pro-angiogenic responses of RASFC, which subsequently altered HUVEC invasion and migration, angiogenic tube formation and the release of pro-angiogenic mediators. In vivo markers of angiogenesis (vascular endothelial growth factor, angiopoietin 2 [Ang2], tyrosine kinase receptor [Tie2]) were significantly associated with oxidative damage and oxygen metabolism in the inflamed synovium. Significant reduction in ST vascularity and Ang2/Tie2 expression was demonstrated in patients with RA before and after administration of TNFi.

Conclusions

Oxidative stress promotes metabolism in favour of glycolysis, an effect that may contribute to acceleration of inflammatory mechanisms and subsequent dysfunctional angiogenesis in RA.

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Title: Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis
Authors: Emese Balogh
Douglas J. Veale
Trudy McGarry
Carl Orr
Zoltan Szekanecz
Chin-Teck Ng
Ursula Fearon
Monika Biniecka
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-018-1592-1

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Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis

Abstract

Background

Methods

Results

Conclusions

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Abstract

Background

Methods

Results

Conclusions

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